Abstract
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
Original language | English (US) |
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Pages (from-to) | 940-952 |
Number of pages | 13 |
Journal | Cancer Cell |
Volume | 30 |
Issue number | 6 |
DOIs | |
State | Published - Dec 12 2016 |
Keywords
- ARQ761
- NQO1
- NQO1 bioctivatable drugs
- NSCLC
- Olaparib
- PARP1
- PDA
- ROS
- Rucaparib
- combination chemotherapy
- synthetic lethality
- β-lapachone
ASJC Scopus subject areas
- Oncology
- Cancer Research